Abstract
Modulation of opioid receptors is the primary choice for pain management and structural information studies have gained new horizons with the recently available X-ray crystal structures. Herkinorin is one of the most remarkable salvinorin A derivative with high affinity for the mu opioid receptor, moderate selectivity and lack of nitrogen atoms on its structure. Surprisingly, binding models for herkinorin are lacking. In this work, we explore binding models of herkinorin using automated docking, molecular dynamics simulations, free energy calculations and available experimental information. Our herkinorin D-ICM-1 binding model predicted a binding free energy of −11.52 ± 1.14 kcal mol−1 by alchemical free energy estimations, which is close to the experimental values −10.91 ± 0.2 and −10.80 ± 0.05 kcal mol−1 and is in agreement with experimental structural information. Specifically, D-ICM-1 molecular dynamics simulations showed a water-mediated interaction between D-ICM-1 and the amino acid H2976.52, this interaction coincides with the co-crystallized ligands. Another relevant interaction, with N1272.63, allowed to rationalize herkinorin’s selectivity to mu over delta opioid receptors. Our suggested binding model for herkinorin is in agreement with this and additional experimental data. The most remarkable observation derived from our D-ICM-1 model is that herkinorin reaches an allosteric sodium ion binding site near N1503.35. Key interactions in that region appear relevant for the lack of β-arrestin recruitment by herkinorin. This interaction is key for downstream signaling pathways involved in the development of side effects, such as tolerance. Future SAR studies and medicinal chemistry efforts will benefit from the structural information presented in this work.
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Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK (2012) Nature 485:400–404
Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hubner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK (2013) Nature 504:101–106
Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Nature 485:321–326
Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK (2015) Nature 524:315–321
Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, Kobilka BK, Demene H, Granier S (2015) Nature 524:375–378
Mnpotra JS, Qiao Z, Cai J, Lynch DL, Grossfield A, Leioatts N, Hurst DP, Pitman MC, Song Z-H, Reggio PH (2014) J Biol Chem 289:20259–20272
Brown MF (1994) Chem Phys Lipids 73:159–180
Botelho AV, Huber T, Sakmar TP, Brown MF (2006) Biophys J 91: 4464–4477
Jacobson KA (2015) Biochem Pharmacol in press
Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Trong IL, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Science 289: 739–745
Okada T, Sugihara M, Bondar A-N, Elstner M, Entel P, Buss V (2004) J Mol Biol 342:571–583
Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi H-J, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) Science 318: 1258–1265
Rasmussen SGF, Choi H-J, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VRP, Sanishvili R, Fischetti RF, Schertler GFX, Weis WI, Kobilka BK (2007) Nature 450:383–387
Guindon J, Walczak J-S, Beaulieu P (2007) Drugs 67:2121–2133
Law P-Y, Wong YH, Loh HH (2000) Annu Rev Pharmacol Toxicol 40:389–430
Kane BE, Svensson B, Ferguson DM (2006) AAAPS J 8:E126–E137
Eguchi M (2004) Med Res Rev 24:182–212
Filizola M, Villar HO, Loew GH (2001) J Comput 15:297–307
Surratt CK, Johnson PS, Moriwaki A, Seidleck BK, Blaschak CJ, Wang JB, Uhl GR (1994) J Biol Chem 269:20548–20553
Pogozheva ID, Przydzial MJ, Mosberg HI (2005) AAAPS J 7:E434–E448
Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han G, Xu Q, deWaal PW, Ke J, Tan MHE, Zhang C, Moeller A, West GM, Pascal BD, Eps NV, Caro LN, Vishnivetskiy SA, Lee RJ, Suino-Powell KM, Gu X, Pal K, Ma J, Zhi X, Boutet S, Williams GJ, Messerschidt M, Gati C, Zatsepin NA, Wang D, James D, Basu S, Roy-Chowdhury S, Conrad CE, Coe J, Liu H, Lisova S, Kupitz C, Grotjohann I, Fromme R, Jiang Y, Tan M, Yang H, Li J, Wang M, Zheng Z, Li D, Howe N, Zhao Y, Standfuss J, Diederichs K, Dong Y, Potter CS, Carragher B, Caffrey M, Jiang H, Chapman HN, Spence JCH, Fromme P, Weierstall U, Ernst OP, Katritch V, Gurevich VV, Griffin PR, Hubbell WL, Stevens RC, Cherezov V, Melcher K, Xu HE (2015) Nature 523:561–567
Groer CE, Tidgewell K, Moyer RA, Harding WW, Rothman RB, Prisinzano TE, Bohn LM (2007) Mol Pharmacol 71:549–557
Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Proc Natl Acad Sci USA 99:11934–11939
Labute P, Williams C, Feher M, Sourial E, Schmidt JM (2001) J Med Chem 44:1483–1490
Schapira M, Totrov M, Abgyan R (1999) J Mol Recognit 12:177–190
Abagyan R, Kufareva I (2009) Methods Mol Biol 575:249–279
An J, Totrov M, Abagyan R (2005) Mol Cell Proteom 4:752–761
Abagyan R, Raush R, Totrov M (2013) ICM Manual v.3.7, MolSoft LLC, La Jolla
Wesson L, Eisenberg D (1992) Protein Sci 1:227–235
Metropolis N, Rosenbluth AW, Rosenbluth MN, Teller AH, Teller E (1953) J Chem Phys 21:1087–1092
Zhong H-J, Liu L-J, Chong C-M, Lu L, Wang M, Chan DS-H, Chan PWH, Lee SM-Y, Ma D-L, Leung C-H (2014) PLoS One 9:e92905
Abagyan R, Totrov M (1994) J Mol Biol 235:983–1002
Totrov M, Abagyan R (1997) Proteins 29(S1):215–220
Totrov M, Abagyan R (1999) Derivation of sensitive discrimination potential for virtual ligand screening. In: Proceedings of the third annual international conference on Computational molecular biology. ACM, Lyon, pp 312–320
Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Cassarino TG, Bertoni M, Bordoli L, Schwede T (2014) Nucleic Acids Res 42:W252–W258
Arnold K, Bordoli L, Kopp J, Schwede T (2006) Bioinformatics 22:195–201
Benkert P, Biasini M, Schwede T (2011) Bioinformatics 27:343–350
Cheng J, Sun X, Li W, Liu G, Tu Y, Tang Y (2016) Sci Rep 6:18913
Bartuzi D, Kaczor AA, Matosiuk D (2016) J Chem Inf Model 56:563–570
Klauda JB, Venable RM, Freites JA, O’Connor JW, Tobias DJ, Mondragon-Ramirez C, Vorobyov I, MacKerell AD, Pastor RW (2010) J Phys Chem B 114:7830–7843
MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) J Phys Chem B 102:3586–3616
Jo S, Kim T, Iyer VG, Im W (2008) J Comput Chem 29:1859–1865
Wu EL, Cheng X, Jo S, Rui H, Song KC, Dávila-Contreras EM, Qi Y, Lee J, Monje-Galvan V, Venable RM, Klauda JB, Im W (2014) J Comput Chem 35:1997–2004
Jo S, Lim JB, Klauda JB, Im W (2009) Biophys J 97:50–58
Jo S, Kim T, Im W (2007) PLoS One 2:e880
Brooks BR, Brooks CL, MacKerell AD, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) J Comput Chem 30:1545–1614
Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, Wei S, Buckner J, Jeong JC, Qi Y, Jo S, Pande VS, Case DA, Brooks CL, MacKerell AD, Klauda JB, Im W (2016) J Chem Theory Comput 12:405–413
Tieleman DP, Forrest LR, Sansom MSP, Berendsen HJC (1998) BioChemistry 37:17554–17561
Grossfield A, Pitman MC, Feller SE, Soubias O, Gawrisch K (2008) J Mol Biol 381:478–486
Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, MacKerell AD (2010) J Comput Chem 31:671–690
Vanommeslaeghe K, MacKerell AD (2012) J Chem Inf Model 52:3144–3154
Vanommeslaeghe K, Raman EP, MacKerell AD (2012) J Chem Inf Model 52:3155–3168
Klimovich PV, Shirts MR, Mobley DL (2015) J Comput Aided Mol Des 29:397–411
Bennett CH (1976) J Comput Phys 22:245–268
Roux B, Nina M, Pomès R, Smith JC (1996) Biophys J 71:670–681
Paramo T, East A, Garzón D, Ulmschneider MB, Bond PJ (2014) J Chem Theory Comput 10:2151–2164
Shirts MR, Mobley DL, Chodera JD, Pande VS (2007) J Phys Chem B 111:13052–13063
Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, Rothman RB, Prisinzano TE (2005) J Med Chem 48:4765–4771
Yan F, Mosier PD, Westkaemper RB, Stewart J, Zjawiony JK, Vortherms TA, Sheffler DJ, Roth BL (2005) BioChemistry 44:8643–8651
Kane BE, Nieto MJ, McCurdy CR, Ferguson DM (2006) FEBS J 273:1966–1974
Ballesteros JA, Weinstein H (1995) [19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 25:366–428 (Ed Stuart C. S.). Academic Press
Hevener KE, Zhao W, Ball DM, Babaoglu K, Qi J, White SW, Lee RE (2009) J Chem Inf Model 49:444–460
Yongye AB, Bender A, Martinez-Mayorga K (2010) J Comput Aided Mol Des 24:675–686
Joung JY, Nam K-Y, Cho K-H, No KT (2012) J Chem Inf Model 52:984–995
Martinez-Mayorga K, Byler KG, Yongye AB, Giulianotti MA, Dooley CT, Houghten RA (2013) Eur J Med Chem 66:114–121
Mansour A, Taylor LP, Fine JL, Thompson RC, Hoversten MT, Mosberg HI, Watson SJ, Akil H (1997) J Neurochem 68:344–353
Fowler CB, Pogozheva ID, LeVine H, Mosberg HI (2004) BioChemistry 43:8700–8710
Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC (2014) Trends Biochem Sci 39:233–244
Xu H, Partilla J, Wang X, Rutherford J, Tidgewell K, Prisinzano T, Bohn L, Rothman R (2007) Synapse 61:166–175
Ji F, Wang Z, Ma N, Riley J, Armstead WM, Liu R (2013) Brain Res 1490C:95–100
Schiller PW, Nguyen TMD, Berezowska I, Dupuis S, Weltrowska G, Chung NN, Lemieux C (2000) Eur J Med Chem 35:895–901
Mignat C, Wille U, Ziegler A (1995) Life Sci 56:793–799
Iyer MR, Lee YS, Deschamps JR, Dersch CM, Rothman RB, Jacobson AE, Rice KC (2012) Eur J Med Chem 50:44–54
Peng X, Knapp BI, Bidlack JM, Neumeyer JL (2007) J Med Chem 50:2254–2258
Magnan J, Paterson SJ, Tavani A, Kosterlitz HW (1982) Naunyn-Schmiedeberg’s Arch Pharmacol 319:197–205
Lewanowitsch T, Irvine R (2003) Brain Res 964:302–305
Vortherms TA, Mosier PD, Westkaemper RB, Roth BL (2007) J Biol Chem 282:3146–3156
Polepally PR, Huben K, Vardy E, Setola V, Mosier PD, Roth BL, Zjawiony JK (2014) Eur J Med Chem 85:818–829
Bartuzi D, Kaczor AA, Matosiuk D (2015) J Chem Inf Model 55:2421–2434
Johnson M, Maggiora GM (1990) Concepts and applications of molecular similarity. Wiley, New York
Maggiora GM (2006) J Chem Inf Model 46:1535–1535
Yan F, Bikbulatov RV, Mocanu V, Dicheva N, Parker CE, Wetsel WC, Mosier PD, Westkaemper RB, Allen JA, Zjawiony JK, Roth BL (2009) BioChemistry 48:6898–6908
Spivak CE, Beglan CL, Seidleck BK, Hirshbein LD, Blaschak CJ, Uhl GR, Surratt CK (1997) Mol Pharmacol 52: 983–992
Minami M, Nakagawa T, Seki T, Onogi T, Aoki Y, Katao Y, Katsumata S, Satoh M (1996) Mol Pharmacol 50:1413–1422
González-Andrade M, Rodríguez-Sotres R, Madariaga-Mazón A, Rivera-Chávez J, Mata R, Sosa-Peinado A, Pozo-Yauner LD, Arias-Olguín II (2016) J Biomol Struct Dyn 34:78–91
Horstman DA, Brandon S, Wilson AL, Guyer CA CA, Cragoe EJ EJ, Limbird LE LE (1990) J Biol Chem 265:21590–21595
Neve KA, Cumbay MG, Thompson KR, Yang R, Buck DC, Watts VJ, DuRand CJ, Teeter MM (2001) Mol Pharmacol 60: 373
Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, Ijzerman AP, Cherezov V, Stevens RC (2012) Science 337:232
Shang Y, LeRouzic V, Schneider S, Bisignano P, Pasternak GW, Filizola M (2014) BioChemistry 53:5140–5149
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KMM acknowledge Institute of Chemistry UNAM, for financial support. AFMV acknowledge CONACYT for scholarship.
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Marmolejo-Valencia, A.F., Martínez-Mayorga, K. Allosteric modulation model of the mu opioid receptor by herkinorin, a potent not alkaloidal agonist. J Comput Aided Mol Des 31, 467–482 (2017). https://doi.org/10.1007/s10822-017-0016-7
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DOI: https://doi.org/10.1007/s10822-017-0016-7